Biomarkers that predict clinical response or remission in asthma patients

Abstract

Methods for predicting whether a subject with asthma will respond to asthma therapy and/or will achieve asthma remission using biomarkers are provided. Methods of treating asthma in a subject with an increased expression level of at least one biomarker or a biomarker set are provided. Methods for predicting whether a subject with asthma will respond to asthma therapy and/or will achieve asthma by measuring ciliated cell levels, e.g., epithelial ciliated cell levels and/or epithelial proximal ciliated cell levels, are provided.

1 . A method of treating a chronic airway disease in a subject, comprising selecting a subject having increased goblet cell expression relative to a control and administering to the subject a drug that promotes transdifferentiation of goblet cells into ciliated cells. 
     
     
         2 . The method of  claim 1 , wherein the chronic airway disease is selected from the group consisting of asthma, chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), bronchiectasis, unified airway disease, eosinophilic granulomatosis with polyangiitis (EGPA), gastroesophageal reflux disease (GERD), cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis (EoE), chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP), aspirin hypersensitivity, NSAID exacerbated respiratory disease (NSAID-ERD), perennial allergic rhinitis (PAR), food allergy, and chronic eosinophilic pneumonia (CEP). 
     
     
         3 . The method of  claim 1 , wherein:
 the chronic airway disease is asthma;   the drug is a biologic compound that is selected from the group consisting of dupilumab, benralizumab, mepolizumab, omalizumab, reslizumab and tezepelumab;   the goblet cells are hyperplastic goblet cells;   the ciliated cells are mucous ciliated cells;   airway damage is reversed in the subject after administering the drug;   the subject achieves a decreased Global Initiative for Asthma (GINA) score, an increased asthma control test (ACT) score, or a decrease in number of exacerbations within six months of administering the drug; or   the subject achieves asthma remission, or any combination thereof.   
     
     
         4 - 9 . (canceled) 
     
     
         10 . A method of determining whether a subject is a suitable candidate for drug treatment for a chronic airway disease, or a method of monitoring efficacy of drug treatment in a subject having a chronic airway disease, comprising:
 obtaining a pre-treatment sample from the subject;   treating the subject with the drug; and   obtaining a post-treatment sample from the subject, wherein the subject is determined to be a suitable candidate for treatment if mucous-ciliated cell frequency is increased in the post-treatment sample relative to the pre-treatment sample.   
     
     
         11 . The method of  claim 10 , wherein:
 the pre-treatment and post-treatment samples are nasal brush samples from the subject,   the chronic airway disease is selected from the group consisting of asthma, chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, chronic sinusitis, ABPA, bronchiectasis, unified airway disease, EGPA, GERD, CF, COPD, EoE, CRSwNP, CRSsNP, aspirin hypersensitivity, NSAID-ERD, PAR, food allergy, and CEP;   the chronic airway disease is asthma;   the drug is a biologic compound that is selected from the group consisting of dupilumab, benralizumab, mepolizumab, omalizumab, reslizumab and tezepelumab;   the goblet cells are hyperplastic goblet cells;   the ciliated cells are mucous ciliated cells; or   the subject achieves asthma remission after administering the drug, or any combination thereof.   
     
     
         12 - 24 . (canceled) 
     
     
         25 . A method of screening whether a drug is a suitable treatment for a chronic airway disease, comprising contacting goblet cells with the drug, wherein the drug stimulates transdifferentiation of goblet cells into ciliated cells if the drug is suitable for treating the chronic airway disease, optionally wherein:
 the goblet cells are obtained from nasal brush samples from the subject;   the goblet cells are grown in vitro;   the chronic airway disease is selected from the group consisting of asthma, chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, chronic sinusitis, ABPA, bronchiectasis, unified airway disease, EGPA, GERD, CF, COPD, EoE, CRSwNP, CRSsNP, aspirin hypersensitivity, NSAID-ERD, PAR, food allergy, and CEP;   the chronic airway disease is asthma;   the drug is a biologic compound that is selected from the group consisting of dupilumab, benralizumab, mepolizumab, omalizumab, reslizumab and tezepelumab;   the goblet cells are hyperplastic goblet cells; or   the ciliated cells are mucous ciliated cells, or any combination thereof; or   (II) a bioassay to screen whether a drug is a suitable treatment for a chronic airway disease in a subject, comprising contacting goblet cells from the subject with the drug, wherein the drug stimulates transdifferentiation of goblet cells into ciliated cells if the drug is suitable for treating the chronic airway disease, optionally wherein:   the drug is administered directly to the subject;   the goblet cells are obtained from nasal brush samples from the subject;   the goblet cells are obtained from nasal brush samples from the subject prior to administering the drug and grown in vitro;   the goblet cells grown in vitro are contacted with the drug;   the chronic airway disease is selected from the group consisting of asthma, chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, chronic sinusitis, ABPA, bronchiectasis, unified airway disease, EGPA, GERD, CF, COPD, EoE, CRSwNP, CRSsNP, aspirin hypersensitivity, NSAID-ERD, PAR, food allergy, and CEP;   the chronic airway disease is asthma;   the drug is a biologic compound that is selected from the group consisting of dupilumab, benralizumab, mepolizumab, omalizumab, reslizumab and tezepelumab;   the goblet cells are hyperplastic goblet cells; or   the ciliated cells are mucous ciliated cells, or any combination thereof.   
     
     
         26 - 42 . (canceled) 
     
     
         43 . A method for predicting whether a subject with asthma will respond to asthma therapy, or will achieve asthma remission in response to asthma therapy, comprising:
 measuring an expression level of at least one gene selected from the group consisting of C20orf85, FAM92B, CAPS, MORN5, CAPSL, ZMYND10, SNTN, TCTEX1D2, PIFO, RSPH1, DYNLRB2, C2orf40, SPA17, CCDC170, C11orf88, CETN2, ROPN1L, CCDC78 and C9orf24 in a biological sample from the subject,   wherein an increase in expression level of at least one gene selected from the group consisting of C20orf85, FAM92B, CAPS, MORN5, CAPSL, ZMYND10, SNTN, TCTEX1D2, PIFO, RSPH1, DYNLRB2, C2orf40, SPA17, CCDC170, C11orf88, CETN2, ROPN1L, CCDC78 and C9orf24 relative to a control is an indication that the subject will respond to the asthma therapy, or is an indication that the subject will achieve asthma remission from the asthma therapy; or   (II) a method for predicting whether a subject with asthma will achieve asthma remission in response to asthma therapy comprising:   measuring a ciliated cell gene signature in a biological sample from the subject,   wherein an increase in the ciliated cell gene signature expression levels observed relative to a control is an indication that the subject will achieve asthma remission from the asthma therapy; or   (III) a method of treating asthma in a subject with an increased expression level of a ciliated cell gene signature in a biological sample obtained from the subject relative to a control, comprising selecting the subject with an increased ciliated cell gene signature and administering to the subject asthma therapy.   
     
     
         44 . The method of  claim 43 , wherein:
 the asthma therapy comprises administering a biologic compound to the subject, optionally wherein the biologic compound is selected from the group consisting of dupilumab, benralizumab, mepolizumab, omalizumab, reslizumab and tezepelumab;   the asthma therapy increases Asthma Control Test (ACT) score, reduces Global Initiative for Asthma (GINA) score, and/or decreases risk of exacerbations in the subject; or   the biological sample is a nasal brush sample.   
     
     
         45 - 52 . (canceled) 
     
     
         53 . The method of  claim 1 , wherein the subject has an increased expression level of at least one gene selected from the group consisting of C11orf88, C20orf85, C2orf40, C9orf24, CAPS, CAPSL, CCDC170, CCDC78, CETN2, DYNLRB2, FAM92B, MORN5, PIFO, ROPN1L, RSPH1, SNTN, SPA17, TCTEX1D2 and ZMYND10 in a biological sample obtained from the subject relative to a control, further comprising selecting the subject with the increased expression level and administering to the subject asthma therapy. 
     
     
         54 . The method of  claim 53 , wherein:
 the asthma therapy comprises administering a biologic compound to the subject;   the biologic compound is selected from the group consisting of dupilumab, benralizumab, mepolizumab, omalizumab, reslizumab and tezepelumab;   the asthma therapy increases ACT score, reduces GINA score, and/or decreases risk of exacerbations in the subject; or   the biological sample is a nasal brush sample, or any combination thereof.   
     
     
         55 - 58 . (canceled) 
     
     
         59 . The method of  claim 43 , wherein the ciliated cell gene signature is an epithelial ciliated signature, optionally wherein the epithelial ciliated signature comprises genes selected from the group consisting of FAM92B, CAPSL, C20orf85, C11orf88, SNTN, ROPN1L, ZMYND10, C9orf24, MORN5, CCDC78, CCDC170, RSPH9, C9orf116 and RSPH1. 
     
     
         60 . (canceled) 
     
     
         61 . The method of  claim 43 , wherein the ciliated cell gene signature is an epithelial proximal ciliated signature, optionally wherein the epithelial proximal ciliated signature comprises genes selected from the group consisting of CAPSL, C20orf85, SNTN, CAPS, ROPN1L, PIFO, ZMYND10, C9orf24, MORN5, C2orf40, WDR54, CRIP1, DYNLRB2, SPA17, CES1, C9orf116, RSPH1, TCTEX1D2, TSPAN1, CETN2, TUBB4B and DYNLT1. 
     
     
         62 . (canceled) 
     
     
         63 . The method of  claim 43 , wherein ciliated cell frequency is increased in the subject relative to the control. 
     
     
         64 . The method of  claim 43  wherein the asthma therapy comprises administering a biologic compound to the subject, optionally wherein the biologic compound is selected from the group consisting of dupilumab, benralizumab, mepolizumab, omalizumab, reslizumab and tezepelumab. 
     
     
         65 . (canceled) 
     
     
         66 . The method of claim  60 , wherein:
 the asthma therapy increases ACT score, reduces GINA score, and/or decreases risk of exacerbations in the subject;   the biological sample is a nasal brush sample; or   the ciliated cell gene signature comprises one or more genes selected from the group consisting of FAM92B, CAPSL, C20orf85, C11orf88, CAPS and RSPH9.   
     
     
         67 - 69 . (canceled) 
     
     
         70 . The method of  claim 43 , wherein the ciliated cell gene signature is an epithelial ciliated signature, optionally wherein the epithelial ciliated signature comprises genes selected from the group consisting of FAM92B, CAPSL, C20orf85, C11orf88, SNTN, ROPN1L, ZMYND10, C9orf24, MORN5, CCDC78, CCDC170, RSPH9, C9orf116 and RSPH1. 
     
     
         71 . (canceled) 
     
     
         72 . The method of  claim 43 , wherein the ciliated cell gene signature is an epithelial proximal ciliated signature, optionally wherein the epithelial proximal ciliated signature comprises genes selected from the group consisting of CAPSL, C20orf85, SNTN, CAPS, ROPN1L, PIFO, ZMYND10, C9orf24, MORN5, C2orf40, WDR54, CRIP1, DYNLRB2, SPA17, CES1, C9orf116, RSPH1, TCTEX1D2, TSPAN1, CETN2, TUBB4B and DYNLT1. 
     
     
         73 . (canceled) 
     
     
         74 . The method of  claim 43 , wherein ciliated cell frequency is increased in the subject relative to the control. 
     
     
         75 . The method of  claim 43  wherein the asthma therapy comprises administering a biologic compound to the subject, optionally wherein the biologic compound is selected from the group consisting of dupilumab, benralizumab, mepolizumab, omalizumab, reslizumab and tezepelumab. 
     
     
         76 . (canceled) 
     
     
         77 . The method of claim  69 , wherein:
 the asthma therapy increases ACT score, reduces GINA score, and/or decreases risk of exacerbations in the subject,   the biological sample is a nasal brush sample; or   the ciliated cell gene signature comprises one or more genes selected from the group consisting of FAM92B, CAPSL, C20orf85, C11orf88, CAPS and RSPH9.   
     
     
         78 . (canceled) 
     
     
         79 . (canceled)